Lisinopril is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. Lisinopril also is used in conjunction with other agents such as β-adrenergic blocking agents (β-blockers), cardiac glycosides, and diuretics in the management of heart failure. In addition, lisinopril may be used in conjunction with thrombolytic agents, aspirin, and/or β-blockers to improve survival in patients with acute myocardial infarction (MI) who are hemodynamically stable.
Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects, (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease) or in patients receiving immunosuppressive therapy, the possibility that similar adverse effects may occur with lisinopril should be considered since current evidence is insufficient to rule out such risk.
Lisinopril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. ACE inhibitors are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease, or cerebrovascular disease or following MI. ( and in .)
In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors. Although ACE inhibitors have lowered blood pressure in all races studied, monotherapy with an ACE inhibitor has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension; however, this population difference in response does not appear to occur during combined therapy with an ACE inhibitor and a thiazide diuretic or calcium-channel blocker. In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied. (See ALLHAT study below and also and .)
The ALLHAT study, a large (33,357 patients), multicenter, randomized, active-control study in hypertensive patients 55 years of age or older with at least one other coronary heart disease risk factor, compared the cardiovascular benefit of therapy with an ACE inhibitor (lisinopril 10-40 mg daily) or a dihydropyridine-derivative calcium-channel blocker (amlodipine 2.5-10 mg daily) relative to therapy with a thiazide diuretic (chlorthalidone 12.5-25 mg daily). After a mean follow-up of 4.9 years, an intent-to-treat analysis revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI among the treatments.
Compared with chlorthalidone, the relative risks for the primary outcome were 0.99 for lisinopril and 0.98 for amlodipine. In addition, all-cause mortality, a secondary outcome, did not differ among the treatments. Although each drug decreased blood pressure substantially, the extent of reduction was not equivalent. Five-year systolic blood pressures were significantly higher in the lisinopril (2 mm Hg) and amlodipine (0.8 mm Hg) groups relative to that achieved with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg) relative to the thiazide. Control of hypertension (systolic and diastolic blood pressures less than 140 and 90 mm Hg, respectively) was achieved in approximately two-thirds of patients by 5 years of follow-up (61, 66, or 68% of patients treated with lisinopril, amlodipine, lisinopril, or chlorthalidone, respectively).
Subgroup analysis of the ALLHAT study for race-related effects revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI among the treatments in both black and nonblack patients. However, substantial race-related effects were observed in the incidence of secondary outcomes (e.g., stroke, combined cardiovascular disease events, heart failure). Compared with chlorthalidone, the relative risk for lisinopril was 1.4 or 1 (in black or nonblack patients, respectively) for stroke and 1.19 or 1.06 (in black or nonblack patients, respectively) for combined cardiovascular disease events. When amlodipine was compared with chlorthalidone, the only race-related difference observed was in the incidence of heart failure; the relative risk was 1.46 or 1.32 (in black or nonblack patients, respectively). The relative risk for heart failure in black versus nonblack patients receiving lisinopril was not considered to be statistically significant, and the overall relative risk for both groups was 1.19. In addition, after 4 years, in each treatment group, blood pressure reductions were greater in nonblack than in black patients; about 68 or 60% of nonblack or black patients, respectively, achieved a systolic/diastolic blood pressure of less than 140/90 mmHg. In nonblack patients receiving chlorthalidone, amlodipine, or lisinopril 69, 69, or 67% achieved the mentioned blood pressure, respectively, while in black patients receiving chlorthalidone, amlodipine, or lisinopril 63, 60, or 54% achieved such blood pressure, respectively.
Although the ALLHAT study provides strong evidence that these classes of antihypertensive agents (ACE inhibitors, dihydropyridine-derivative calcium-channel blockers, thiazide diuretics) are comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. Thiazide diuretic therapy was superior to ACE inhibitor therapy in preventing aggregate cardiovascular events, principally stroke, heart failure, angina, and the need for coronary revascularization. Thiazide therapy also was better tolerated than ACE inhibitor therapy (e.g., angioedema, which was more likely in blacks than nonblacks).
Post hoc analysis of the ALLHAT study directly comparing cardiovascular and other outcomes in patients receiving amlodipine or lisinopril revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI between patients receiving the ACE inhibitor and those receiving the calcium-channel blocking agent. However, patients receiving lisinopril were at higher risk for stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving amlodipine were at higher risk of developing heart failure. ALLHAT investigators suggested that the observed differences in cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of amlodipine compared with that of lisinopril, especially in women and black patients.
For additional information on the role of ACE inhibitors in the management of hypertension, and in . For information on overall principles and expert recommendations for treatment of hypertension, .
Lisinopril is used as adjunctive therapy in the management of heart failure in patients who do not respond adequately to diuretics and a cardiac glycoside.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality. If ACE inhibitors are not tolerated, then an angiotensin II receptor antagonist is recommended as alternative therapy. In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of ACE inhibitors in the management of heart failure, and
Some clinicians state that ACE inhibitors usually are prescribed in clinical practice at dosages lower than those determined as target dosages in clinical trials, although results of several studies suggest that high dosages are associated with greater hemodynamic, neurohormonal, symptomatic, and prognostic benefits than lower dosages. Results of a large, randomized, double blind study (Assessment of Treatment with Lisinopril and Survival [ATLAS] study) in patients with heart failure (NYHA class II-IV) indicate that high lisinopril dosages (32.5-35 mg daily) were associated with a 12% lower risk of death or hospitalization for any cause and 24% fewer hospitalizations for heart failure than low dosages (2.5-5 mg) of the drug.
Many patients with heart failure respond to lisinopril with improvement in cardiac function indexes, symptomatic (e.g., dyspnea, fatigue) relief, improved functional capacity, and increased exercise tolerance. In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 3 months. Although additional studies are needed to determine the specific role of lisinopril in the management of heart failure and its long-term efficacy, the efficacy of the drug appears to be similar to that of captopril and enalapril. However, like enalapril, lisinopril has a relatively long duration of action compared with captopril; therefore, the drug may produce more prolonged hypotensive effects, particularly at high doses, which potentially could result in adverse cerebral and renal effects. In addition, because the renin-angiotensin system appears to contribute substantially to preservation of glomerular filtration in patients with heart failure in whom renal function is severely compromised, therapy with an ACE inhibitor may adversely affect renal function. ( and in .)
Mortality Reduction After Acute Myocardial Infarction
Lisinopril is used in conjunction with standard therapies (e.g., thrombolytic agents, aspirin, β-blockers) to improve survival in hemodynamically stable patients with acute MI. Results of a multicenter, controlled, randomized, clinical study indicate that patients who received lisinopril or lisinopril concomitantly with nitrates within 24 hours of MI in addition to conventional therapy (thrombolytic agents, aspirin, β-blockers) had an 11% lower risk of death (6 weeks after infarction) compared with patients receiving conventional therapy only; mortality rates were 6.4 or 7.2% in patients receiving lisinopril and conventional therapy or conventional therapy alone, respectively.
Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI. The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia). In addition to their effects on mortality, ACE inhibitors also are used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular ''remodeling'') following acute MI. Evidence regarding the efficacy of such therapy has been somewhat conflicting, particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction. However, the preponderance of evidence has shown a benefit of early oral therapy with ACE inhibitors, even in patients with no baseline dysfunction.
Current expert guidelines recommend the use of an ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction). While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction. ACE inhibitor therapy generally should be continued indefinitely in all patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, chronic kidney disease). The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.
Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed. For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see